Editorial

Autoimmunity is present both in some rheumatic diseases and
in cancer with a bidirectional interaction [1]. Cancer can
induce, for example: an auto-antigen mutation with production
of autoantibodies against self-tissue targets, favoring the onset
of an autoimmune disease. On the other hand, patients affected
by autoimmune rheumatic diseases have a higher risk of cancer
compared to the general population. Emblematic is the risk of
onset of lymphoma in patients affected by Sjogren’s syndrome.
In these patients, the related risk for non-Hodgkin’s lymphoma
(NHL) and mucosa- associated lymphoid tissue (MALT) NHL
is generally estimated at 10 to 15 times when compared to the
general population [2]. The chronic inflammatory stimulus, a
common genetic predisposition with a family history of both
cancer and autoimmune diseases, the use of
immunosuppressive drugs are considered the most relevant
favoring factors [3,4]. The occurrence of specific clinical
pictures must be considered a neoplastic warning [5].

Systemic sclerosis (SSc) is an autoimmune endotheliopathy
compromising the function of almost any organ in consequence
of an ischemic damage and excessive collagen storage.
Sclerosis of the skin (so-called scleroderma) can be not present
(SSc sine scleroderma). Usually, Raynaud’s phenomenon is the
first manifestation; other clinical manifestations can appear
several years after. Autoantibodies are found in 95-98% of SSc
patients. The three most common autoantibodies are: anticentromere,
anti-topoisomerase I and anti-RNA polymerase III
(RNAP III). They are associated with distinct clinical
phenotypes and prognosis: in particular, RNAP III antibodies
are present in patients with rapidly progressive cutaneous
involvement and higher risk of cancer-associated SSc. As
already underlined, all patients affected by autoimmune
rheumatic disease such as SSc have an increased cancer risk
compared to the general population but SSc patients with
RNAP III antibodies positivity have a significant risk to
develop cancer in a short time (6 months-1 year, on average)
[6]. Sometimes, SSc and cancer are synchronous. An analysis
restricted to this specific subset highlighted that these patients
are older at scleroderma onset, more often male and with
diffuse cutaneous involvement. SSc patients with presence of
RNAP III antibodies present a unique nucleolar RNAP III
expression pattern in their cancerous tissues and this pattern is
detected neither in SSc patients with presence of others
different autoantibodies nor in normal control tissues [7]. In
conclusion, in these patients SSc represents a paraneoplastic
picture.

Some investigators noted almost two possible alterations in the
gene encoding RNAP III (POLR3A gene locus): in some cases,
somatic mutations changing a single amino acid; in other cases,
loss of heterozygosity. The final result of these alterations is a
tumor antigen inducing a targeting immune response with
production of antibodies cross-reacting with the wild type
protein present in scleroderma target tissues [8]. Every
malignancy can be diagnosed in these patients but it is also
possible that no cancer is detected because the anti-tumor
immune response may eradicate an occult malignancy: in these
cases, the occult malignancy represented only the start-point of
the autoimmunity leading to SSc.

Another subset of cancer-associated SSc is represented by
patients with presence of autoantibodies against RNA binding
region containing 3 (RNPC3). RNPC3 is a member of the
minor spliceosoma complex that participates in removal of
U12-type introns from pre-mRNA [9]. These antibodies are not
present in cancer patients without autoimmune rheumatic
diseases different from SSc and are not present in other
rheumatic diseases [10]. The patients affected by SSc with
RNPC3 antibodies have not antinuclear, anticentromere,
antitopoisomerase I and anti RNAP III antibodies. Even in this
subset of SSc patients, every malignancy can be diagnosed but
must be underlined that fifty percent of malignancies are breast
cancer. Many investigators underlined an increased risk of
breast cancer in patients with SSc but only few studies
suggested a possible causal relationship between these two
diseases. Furthermore, breast cancer is not the most frequent
type of malignancy in SSc patients. So, this association must be
well highlighted.

Age at scleroderma onset >65 years has been documented as
independent factor for autoimmunity in cancer-associated SSc
[11] with so-called immunosenescence as favoring factor [12].

In conclusion, autoimmunity has a relevant rule in cancerassociated
SSc and has significant implications for malignancy
screening. In SSc patients with presence of RNAP III and
RNPC3 antibodies, more extensive imaging such as
computerized tomography (CT) of the chest, abdomen, pelvis,
breast or whole body positron emission tomography associated
with CT, and laboratory markers should be considered,
regardless of the presence or not of other risk factors. In the
clinical practice, we must take into account that we could find
any malignancy, as discussed above.

The presence of age at scleroderma onset >65 years, a rapidly
progressive cutaneous involvement, the presence of constitutional manifestations such as weight loss or fever of
unknown origin, a personal or family history of cancer
represent another “red flags” (Table 1). In SSc patients with
positivity for RNPC3 antibodies, screening for breast cancer is
mandatory.

1.

Positivity of RNAP III or RNPC3 antibodies

2.

Age at scleroderma onset >65 years

3.

Rapidly progressive cutaneous involvement

4.

Constitutional manifestations

5.

Personal or family history of cancer

The presence of only one point is sufficient. More points are present, more aggressive must be cancer surveillance

On the other hand, in SSc patients without positivity of RNAP
III or RNPC3 antibodies, a comprehensive physical
examination associated with basal laboratory data can be
considered as a sufficient first step and a targeted screening
should be considered only in presence of specific risk factors.